Derangements in the cell cycle machinery contribute to uncontrolled cell growth and tumorigenesis. Regulators of GI progression including cyclin D1 and the cyclin-dependent kinase inhibitors p21 and p27 appear to be of particular importance in the pathogenesis of breast cancer. Our data show that the overexpression of cyclin D1 leads to a compensatory increase in the cdk inhibitor p21, and suggest that this increase can weaken the value of cyclin D1 overexpression as a diagnostic indicator. We suggest that aggressive breast cancer will involve both (1) overexpression of cyclin D1 and (2) the failure to undergo a compensatory upregulation of cdk inhibitors. The specific aims are designed to test these hypotheses in cell culture models, nude mice, and breast cancer biopsies. We have thus far determined that p21- null fibroblasts are adhesion-dependent and suitable for use to study the role of p21 in negating the effect of cyclin D1 overexpression on anchorage-independent cell cycle progression. We have also stably transfected cells with a tetracycline-regulated cyclin D1 to further address this issue. Finally, we have optimized the conditions for the immunohistochemical analysis of human breast cancer tissue for cyclin D1 and p27 expression.

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